Iran J Reprod Med Vol. 13. No. 7. pp: 387-396, July 2015
Review article
Thyroid dysfunction and pregnancy outcomes Sima Nazarpour1 Ph.D. Candidate, Fahimeh Ramezani Tehrani2 M.D., Masoumeh Simbar1 Ph.D., Fereidoun Azizi3 M.D. 1. Department of Reproductive Health, Faculty of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Corresponding Author: Fahimeh Ramezani Tehrani, Research Institute for Endocrine Sciences, 24 Parvaneh, Yaman St., Velenjak, Tehran, Iran. P.O.Box: 19395-4763. Email: [email protected]; [email protected] Tel: (+98) 21-22409309 Received: 4 March 2014 Revised: 30 November 2014 Accepted: 18 March 2015
Abstract Background: Pregnancy has a huge impact on the thyroid function in both healthy women and those that have thyroid dysfunction. The prevalence of thyroid dysfunction in pregnant women is relatively high. Objective: The objective of this review was to increase awareness and to provide a review on adverse effect of thyroid dysfunction including hyperthyroidism, hypothyroidism and thyroid autoimmune positivity on pregnancy outcomes. Materials and Methods: In this review, Medline, Embase and the Cochrane Library were searched with appropriate keywords for relevant English manuscript. We used a variety of studies, including randomized clinical trials, cohort (prospective and retrospective), case-control and case reports. Those studies on thyroid disorders among non-pregnant women and articles without adequate quality were excluded. Results: Overt hyperthyroidism and hypothyroidism has several adverse effects on pregnancy outcomes. Overt hyperthyroidism was associated with miscarriage, stillbirth, preterm delivery, intrauterine growth retardation, low birth weight, preeclampsia and fetal thyroid dysfunction. Overt hypothyroidism was associated with abortion, anemia, pregnancy-induced hypertension, preeclampsia, placental abruption, postpartum hemorrhage, premature birth, low birth weight, intrauterine fetal death, increased neonatal respiratory distress and infant neuro developmental dysfunction. However the adverse effect of subclinical hypothyroidism, and thyroid antibody positivity on pregnancy outcomes was not clear. While some studies demonstrated higher chance of placental abruption, preterm birth, miscarriage, gestational hypertension, fetal distress, severe preeclampsia and neonatal distress and diabetes in pregnant women with subclinical hypothyroidism or thyroid autoimmunity; the other ones have not reported these adverse effects. Conclusion: While the impacts of overt thyroid dysfunction on feto-maternal morbidities have been clearly identified and its long term impact on childhood development is well known, data on the early and late complications of subclinical thyroid dysfunction during pregnancy or thyroid autoimmunity are controversial. Further studies on maternal and neonatal outcomes of subclinical thyroid dysfunction maternal are needed. Key words: Thyroid disease, Pregnancy outcome, Hypothyroidism, Hyperthyroidism. This article extracted from Ph.D. thesis. (Sima Nazarpour)
Introduction hyroid hormones have profound variation during the life span and are associated with severe adverse health impacts (1, 2). Pregnancy, as an important reproductive event, has a profound but reversible effect on the thyroid gland and its functions. Pregnancy is actually a state of excessive thyroid stimulation leading to an increase in thyroid size by 10% in iodide sufficient areas and 20-40% in iodide deficient regions (3). Furthermore following the physiological and hormonal changes caused by pregnancy and human chorionic gonadotropin (HCG) the production of thyroxin
T
(T4) and triiodothyronine (T3) increase up to 50% leading to 50% increase in a woman’s daily iodide need, while Thyroid-stimulating hormone (TSH) levels are decreased, especially in first trimester (4). In an iodide sufficient area, these thyroid adaptations during pregnancy are well tolerated, as stored inner thyroid iodide is enough; however in iodide deficient areas, these physiological adaptations lead to significant changes during pregnancy (5). Furthermore in women who suffered from thyroid dysfunction prior to pregnancy, the hormonal changes mentioned are magnified, leading to possibly adverse pregnancy outcomes if not been treated appropriately. Furthermore the mode of delivery may
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additionally have adverse impact on fetalpituitary- thyroid axis (6). The prevalence of thyroid dysfunction in pregnant women is relatively high so that overt thyroid dysfunction occurs in 2-3% of pregnancies, and subclinical dysfunction in 10% of pregnancies (7) and thyroid autoimmunity is even more prevalent (8). Given the high prevalence of thyroid disturbances in pregnancy and lack of adequate review article summarizing the effect of thyroid dysfunction on pregnancy and neonatal outcomes, we aimed to summarize the adverse effects of thyroid dysfunction including hyperthyroidism, hypothyroidism and thyroid autoimmune positivity on pregnancy outcomes. Research question was: "are thyroid disorders in pregnant women associated with adverse effects on pregnancy outcomes"? Evidence acquisition This review study was conducted with a prospective protocol. We searched Medline (1985-2013), Embase (1985-2013) and the Cochrane Library (2012) for relevant English manuscripts. Using keywords including “thyroid”, “thyroid dysfunction”, “thyroid disorder”, “hyperthyroidism”, “hypothyroidism”, “euthyroidism”, “subclinical hypothyroidism”, “subclinical hyperthyroidism”, “thyroid autoantibodies”, “pregnancy outcome”, “miscarriage”, “abortion”, “pregnancy loss”, “preterm”, “premature”, “early labor”, “Thyroid peroxidase” and “cognitive” to generate a subset of citations relevant to our research question. Subclinical hypothyroidism (SCH) is defined as a serum TSH level above the
upper limit of normal despite normal levels of serum free thyroxine and subclinical hyperthyroidism is defined as serum thyroid hormone levels within their respective reference ranges in the presence of lowundetectable serum TSH levels (9). Overt hypothyroidism is defined as a serum free T4 level lower than the upper limit of normal and overt hyperthyroidism is defined as a serum free T4 level above the upper limit of normal. Thyroid autoimmunity is defined as increase in thyroid auto antibodies above the upper limit of normal with or without thyroid disturbances. The full manuscripts of all citations that met our study objective were selected and obtained. In cases of duplicate publications, we selected the most recent and complete versions. From the 4480 citations identified from electronic searches, at the beginning, we found 512 related articles; 130 studies on overt hypothyroidism, 203 on subclinical hypothyroidism, 69 on overt hyperthyroidism, 43 on subclinical hyperthyroidism, and 67 on thyroid immunity. Of these articles, 58 met our study objectives, including 11 on hyperthyroidism, 22 on hypothyroidism and 26 on thyroid immunity. We included all qualified original articles on our study subject; including randomized clinical trials, cohort (prospective and retrospective), case-control and case reports. We excluded non-English manuscript, those conducted on non-pregnant women and those with poor quality methodology. The titles and abstracts of all of the studies were evaluated by two non-dependent persons and those met inclusion criteria were appraised.
512 Articles on thyroid dysfunctions
Overt hypothyroidism n=130
Subclinical hypothyroidism n=203
Overt hyperthyroidism n=69
Hypothyroidism In pregnancy n=22
Subclinical hyperthyroidism n=43
Hyperthyroidism In pregnancy n=11
Thyroid immunity n=67
Thyroid immunity In pregnancy n=26
Figure 1. The number of articles that were reviewed in the study.
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Results Hyperthyroidism and its adverse pregnancy and neonatal outcomes The natural physiological changes during pregnancy can mimic some of the signs observed in hyperthyroidism, including increased in basal metabolism, heart rate, fatigue, anxiety, palpitations, heat intolerance, warm and wet skin, hand tremors and systolic murmur; as a result the diagnosis of hyperthyroidism during pregnancy could cause clinical difficulties (9-11). Pregnant women, who suffer from hyperthyroidism, have more severe tachycardia and thyromegaly, along with exophthalmia, and lack of weight gain despite receiving adequate food (10). Overt hyperthyroidism during pregnancy was not prevalent and was reported in 2 out of 1000 pregnancies (0.2%), while subclinical hyperthyroidism was occurred in 1.7% of pregnancies (11, 12). The most prevalent reason for hyperthyroidism during pregnancy was the transient hyperthyroidism resulting from hyperemesis gravidarum (THHG) due to the thyroid stimulation of beta-HCG (13); it was more prevalent in Asian populations compared to Europeans (14). Except for THHG, the etiologies of thyrotoxicosis during pregnancy are the same as for non-pregnant women; it is most prevalent in Grave’s Disease caused by thyrotropin receptor antibodies stimulating the thyroid (TRabs) (11, 15). It is well documented that overt hyperthyroidism has several adverse effects on pregnancy outcomes, e.g. miscarriage, stillbirth, preterm delivery, intrauterine growth retardation, preeclampsia (11, 16). Furthermore women with Graves' disease have antibodies that can stop or stimulate the fetal anti-TSH receptor of thyroid gland (15, 17, 18). There is no consensus regarding the adverse effect of subclinical hypothyroidism on pregnancy or neonatal outcomes. Casey et al. reported no significant increase of placenta abruption, preterm labor and low birth weight in pregnancy complicated by subclinical hyperthyroidism in comparison with euthyroid ones (19). Table I summarizes the results of the most relevant studies on the impact of overt and subclinical hyperthyroidism on pregnancy and neonatal outcomes.
Hypothyroidism and its adverse pregnancy and fetal outcomes Pregnancy can imitate some of the signs that are observed in hypothyroidism, including fatigue, anxiety, constipation, muscle cramps, and weight gain; as a result, the clinical diagnosis of hypothyroidism during pregnancy may be difficult (10, 27). Moreover, most signs of hypothyroidism can be hidden by a woman’s status following the increase in metabolism in pregnancy. Furthermore the thyroid hormonal profile in normal pregnancy can be mis-interoperated as hypothyroidism and as a result the interpretation of thyroid function tests needs trimester-specific reference intervals for a specific population (14, 15). Applying trimester-specific reference ranges of thyroid hormones prevents misclassification of thyroid dysfunction during pregnancy. Compared to hyperthyroidism, hypothyroidism is very common during pregnancy; 2-3% of pregnant women suffer from hypothyroidism (0.3-0.5% overt hypothyroidism and 2-2.5% subclinical hypothyroidism) (11, 28). While the main etiology for hypothyroidism during pregnancy worldwide is iodide insufficiency, however in iodide sufficient areas its main cause is autoimmune thyroiditis (8). SCH is the most common thyroid dysfunction during pregnancy (11, 29). Its prevalence varies between 1.5-5% based on various definitions, different ethnicity, iodine consumption and nutrition life style as well as study designs (30). While the adverse effects of SCH accompanied with positive TPO antibodies or overt hypothyroidism on pregnancy outcome are well known, however there is controversy on negative impact of SCH without autoimmunity on pregnancy outcomes (27, 31-33). Pregnant women that possess the TPO antibodies during the initiation of their pregnancy are subjected to subclinical hypothyroidism during their pregnancy or thyroid dysfunction after childbirth (12). Table II and III summarize the studies on adverse outcomes of overt and subclinical hypothyroidism, respectively. As it has been shown the overt hypothyroidism is associated with increase in prevalence of abortion, anemia, pregnancy-induced hypertension, preeclampsia, placental abruption, postpartum hemorrhage, premature birth, low birth weight,
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intrauterine fetal death and neonatal respiratory distress (15, 27, 29, 32, 34-41). There is no consensus on adverse impacts of subclinical hypothyroidism on pregnancy outcomes; while some studies demonstrated higher chance of placental abruption, preterm birth, miscarriage, gestational hypertension, fetal distress, severe preeclampsia and neonatal distress and diabetes, the other study have not reported and adverse effect (31, 33, 42, 43, 45, 46). The long term effect of overt hypothyroidism on cognitive function has been well documented; these children have lower IQ and more developmental dysfunction (8, 12, 15, 38-41, 46-48), however there is no consensus on the long term cognitive effects of subclinical hypothyroidism; while some reported loss of motor function and intelligence in infants and children the other reported a normal motor and cognitive function (15, 45, 48, 50, 51). Table IV summarizes the cognitive function of infants and children been affected by overt or subclinical hypothyroidism during pregnancy. Autoimmune thyroid disorders Anti-thyroid antibodies are relatively common among women during their reproductive ages, 6-20% of all euthyroid
women are positive for anti-thyroid antibodies (8). The presence of anti-thyroid antibodies during a woman’s reproductive age is not necessarily followed by a thyroid dysfunction and 10-20% of all pregnant women who are TPO antibody positive remain euthyroid in first trimester (3, 56). Despite the high prevalence of TPO antibody positive among reproductive age women, there is no consensus on the feto-maternal complications of euthyroid pregnant women who are TPO antibody positive. As a result, routine screening of pregnant women for thyroid antibodies is controversial (57, 58). Table 7 summarizes the results of the most relevant studies regarding the feto-maternal outcomes of thyroid autoimmune positivity in euthyroid women. While adverse outcomes such as abortion, preterm delivery, recurrent miscarriage, hypertension, fetal dyspenea and diabetes are reported in some of studies, other studies report compatible pregnancy outcomes (27, 40, 44, 45, 46, 59-66). Furthermore Ghassabian and Tiemeier showed that the high titration of anti-thyroid peroxidase antibodies (TPO-Ab) during pregnancy associated with an increased risk of cognitive and behavioral problems in preschool children (67).
Table I. The adverse effects of hyperthyroidism (overt/subclinical) on pregnancy and neonatal outcomes Authors
Year of publication
Location
Type of study
Participants
Outcome
Overt hyperthyroidism Davis et al. (20) Kriplani et al. (21)
1989
USA
Prospective
60 Pregnant women with overt thyrotoxicosis
small for gestational age births, stillbirths, and possibly congenital malformations Preterm labor, pregnancy induced hypertension thyroid crisis, intrauterine growth retardation. Abnormal Thyroid status of neonates.
1994
India
Prospective
32 pregnancies complicated by hyperthyroidism
1994
USA
Retrospective
181 hyperthyroid pregnant women
Low birth weight infants and severe preeclampsia.
2001
Thailand
Retrospective
293 pregnant women with present and past history of hyperthyroidism
Low birth weight
Peleg et al. (18)
2002
USA
Retrospective
Twenty-nine women with a history of Graves disease and positive thyroid-stimulating immunoglobulin
Neonatal thyrotoxicosis
Polak et al. (17)
2004
France
Prospective
72 pregnant women with a history of Graves' disease.
Fetal goiter
Luton et al. (24)
2005
France
prospective
72 pregnant women (72 fetuses)
One fetus had moderate hypothyroidism (1 fetus), goiter (11 fetuses at 32 weeks), and fetal thyroid dysfunction
Luewan et al. (25)
2011
Thailand
Prospective (cohort)
540 pregnant women (180 with hyperthyroidism and 360 controls)
Fetal growth restriction, preterm birth and low birth weight, tendency to have a higher rate of pregnancy-induced hypertension.
Männistö et al. (26)
2013
USA
Retrospective (cohort)
223512 singleton pregnancies
Preeclampsia, superimposed preeclampsia, preterm birth, induction, neonatal intensivecare unit admission
USA
Prospective (cohort)
Millar et al. (22) Phoojaroench anachai et al. (23)
Casey et al. (19)
390
2006
Subclinical hyperthyroidism A total of 25,765 women underwent thyroid screening and 433 women were considered to have subclinical hyperthyroidism
Subclinical hyperthyroidism is not associated with adverse pregnancy outcomes
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Table II. The adverse effects of overt hypothyroidism on pregnancy outcomes Authors
Year of publication
Location
Type of study
Participants
Outcomes Abortion, premature delivery
Abalovich et al (35)
2002
Argentina
Randomized Clinical Trial
114 women with primary hypothyroidism (16 overt hypothyroidism)
Wolfberg et al (37)
2005
USA
Retrospective
19,969 women (482 with treated hypothyroid disease and 19,487 without thyroid disease)
Pre-eclampsia
Idris et al (36)
2005
England
Retrospective
167 pregnant women
Low birth weight caesarean section
Cleary Goldman et al (33)
2008
USA
Prospective
10,990 pregnant women
Preterm labor , macrosomia, gestational diabetes
Sahu et al (32)
2010
India
Prospective
633 pregnant women
Pregnancy-induced hypertension, intrauterine growth restriction, intrauterine demise, Neonatal complications, gestational diabetes
Hirsch et al (38)
2013
Israel
Retrospective case series
306 pregnant women (101 with hyperthyroidism and 205 euthyroid)
Abortions and premature delivery
223512 singleton pregnancies
Primary hypothyroidism: Preeclampsia, superimposed preeclampsia, gestational diabetes, preterm birth, induction , cesarean section, intensive-care unit admission Iatrogenic hypothyroidism: placental abruption , breech presentation, cesarean section after spontaneous labor
Männistö et al (26)
2013
USA
Retrospective
Table III: The adverse effects of subclinical hypothyroidism (with/without thyroid autoimmunity) on pregnancy outcomes Year of publication
Location
2002
Argentina
2005
USA
Prospective (nested-case control)
953 women
Very preterm delivery
2005
USA
Prospective
25,756 women
Placental abruption Preterm birth
ClearyGoldman et al (33)
2008
USA
Prospective
10,990 patients
Subclinical hypothyroidism was not associated with adverse outcomes.
Sahu et al (32)
2010
India
Prospective
633 women
Cesarean section rate for fetal distress
Wilson et al (31)
2012
USA
Prospective
24,883 women
Severe preeclampsia
Authors
Abalovich et al (35) StagnaroGreen et al (42) Casey et al (29)
Negro et al (27)
Benhadi et al (43)
Karakosta et al (44)
2006
2009
2012
Type of the Participants study Subclinical hypothyroidism without control of TPOAb 114 women with primary hypothyroidism (35 subclinical Prospective hypothyroidism
Outcomes
Abortion, premature delivery
Subclinical hypothyroidism including negative and positive TPO Ab Pregnant women who are positive for TPOAb develop impaired thyroid Randomized Italy 984 pregnant women function, increased risk of miscarriage Clinical Trial and premature deliveries Netherlan ds
Greece
prospective (cohort)
prospective
2497 women
Pregnant women without overt thyroid dysfunction, the risk of child loss increased with higher levels of maternal TSH
1170 pregnant women
Increased gestational diabetes and low birth weight neonates among those with of high TSH and spontaneous preterm among those without elevated TSH levels
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Table IV: The cognitive function of infants and children been affected by overt or subclinical hypothyroidism during pregnancy Authors
Year of publication
Location
Type of the study
Participants
Result
Overt hypothyroidism Liu et al (52)
1994
China
All children showed normal IQs Adversely affect their children's
Haddow et al (39)
1999
England
Prospective (cohort)
25216 women
subsequent performance on neuropsychological tests.
125 children of women with Pop et al (47)
2003
Netherlan ds
Prospective
hypothyroxinaemia (63 cases and 62
Delay in infant neurodevelopment.
controls) 204 (108 neonates who were born to
Kooistra et al (48)
2006
Netherlan
Retrospective
ds
(case control)
mothers with hypothyroidism and 96 control)
Lower scores on the Neonatal Behavioral Assessment Scale and orientation index
213 (18 isolated subclinical Li et al (50)
2010
China
Prospective
hypothyroidism, 19 hypothyroxinaemia,
Lower motor and intellectual
(cohort)
34 euthyroid TPOAb positive and 142
development at 25-30 months.
controls) Prospective Henrichs et al (49) Chevrier et al (53)
2010
2011
Netherlan ds
USA
(Population-
Higher risk of expressive language and 3659 children and their mothers
nonverbal cognitive delay
based cohort) Prospective (cohort)
No adverse effect on child 287 pregnant women and their children
neurodevelopment. Children had average or above average results on all parameters. Comparative scores of the neuropsychological tests in
Downing et al (54)
2012
USA
Case report
Three women with hypothyroidism
sibling pairs for full-scale IQ and performance IQ were variable; some scores were higher and some lower in children with congenital hypothyroidism. The development scores (the TsumoriInage Infant's Developmental Test or the
Momotani et al (55)
2012
Japan
Case report
Five women with overt hypothyroidism
Wechsler Intelligence Scale) of all the children turned out to be either normal or advanced.
Subclinical hypothyroidism 213 (18 isolated subclinical Li et al (50)
2010
China
Prospective
hypothyroidism, 19 hypothyroxinaemia ,
Lower motor and intellectual
(cohort)
34 euthyroid TPOAb positive and 142
development at 25-30 months.
controls) Prospective
Ghorbani Behrooz et al (51)
392
2012
Iran
(Historical cohort)
62 children of mothers who had
No adverse effect on IQ level and
subclinical hypothyroidism
cognitive performance of children
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Table V. The feto-maternal outcomes of thyroid autoimmune positivity in euthyroid pregnant women Year of publication
Location
Type of Study
Participants
Outcome
StagnaroGreen et al (68)
1990
USA
Prospective
552 pregnant women
Increased miscarriage
Glinoer et al (40)
1991
Belgium
Prospective
120 euthyroid pregnant women
Increased spontaneous abortion
Pratt et al (64)
1993
USA
Retrospective (case control)
45 women and 100 apparently health blood donors served as controls.
Increased recurrent spontaneous abortions
Glinoer et al (41)
1994
Belgium
Prospective
87 healthy pregnant women with thyroid antibodies and normal thyroid function
Increased spontaneous miscarriage and premature deliveries
Bussen et al (63)
1995
Germany
Retrospective
66 women (22 euthyroid non-pregnant habitual aborters; 22 nulligravidae and 22 multigravidae without endocrine dysfunction as controls).
Increased habitual abortions
Singh et al (69)
1995
Iijima et al (70)
1997
Authors
USA
Japan
Retrospective Prospective
487 subfertile women who had undergone Assisted reproductive technology 1, 179 healthy pregnant women including 228 cases of positive thyroid autoantibody
Increased miscarriage Increased spontaneous abortion
1999
USA
Retrospective.
1588 women (700 women with a history of pregnancy losses, 688 women with a history of infertility who were undergoing Assisted reproductive technology, and 200 healthy, reproductive-aged female controls)
1999
Netherlan ds
Prospective (nested-case control)
173 subfertile women undergoing Invitro fertilization
No increase of miscarriage in women without a history of habitual abortion
Dendrinos et al (60)
2000
Greece
Retrospective (case control)
45 women (30 euthyroid with Recurrent spontaneous miscarriage and 15 matched controls)
Increased recurrent spontaneous miscarriage
Bagis et al (59)
2001
Turkey
Retrospective
876 women
Poppe et al (71)
2003
Kutteh et al (62)
Muller et al (66)
Marai et al (72) StagnaroGreen et al (42) Negro et al (27) Ghafoor et al (73)
Retrospective (case control) Prospective (nested-case control) Randomized Clinical Trial
Pakistan
Prospective
1, 500 pregnant women
2007
Italy
Retrospective
416 euthyroid women (42 were positive TPOAb) undergoing Assisted reproductive technology
Increased unsuccessful pregnancy or subsequent miscarriage
2008
Iran
Retrospective (case-control)
641 women with a history of 3 or more consecutive pregnancy losses and 269 controls
Increased recurrent abortion
2008
USA
Prospective
10,990 pregnant women
Increased preterm premature rupture of membranes
2009
Finland
Prospective
9, 247 singleton pregnancies
Increased perinatal death
Iran
Retrospective (case control)
95 cases as fertile controls and 70, 78 and 137 cases with infertility and recurrent abortion respectively.
Increased recurrent abortion
USA
Prospective
10, 062 singleton pregnancies
2011
Italy
Prospective
3593 pregnant women
2011
India
Prospective
483 pregnant women
Israel
2005
USA
2006
Italy
2006
Negro et al (46) Iravani et al (74)
Soltanghora ee et al (76) Haddow et al (77) Negro et al (78) Nambiar et al (61) Ashoor et al (65) Karakosta et al (44)
Increased abortion
234 subfertile women undergoing Assisted reproductive technology 66 women (58 with impaired fertility and 28 control parous women) 124 Cases and 124 Controls were randomly selected from among the 953 women who delivered at term 984 pregnant women (TPO Ab + & -, euthyroid & subclinical)
Belgium
2004
ClearyGoldman et al (33) Männistö et al (75)
Increased recurrent pregnancy loss
2010 2010
Prospective,
2011
Europe
Prospective
4, 420 singleton pregnancies
2012
Greece
Prospective
1170 pregnant women (TPO Ab + & - , euthyroid & subclinical)
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Increased miscarriage Increased recurrent miscarriages Increased very preterm delivery Increased miscarriage and premature deliveries Increased low-birth-weight of neonates and high abortion rate
Increased preterm delivery, premature rupture of membranes Increased very preterm delivery and respiratory distress Increased miscarriage No increase spontaneous early preterm delivery Increased gestational diabetes and low birth weight neonates among those with of high TSH and spontaneous preterm among those without elevated TSH levels
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Conclusion
Conflict of Interests
Although it is well documented that overt hypothyroidism and overt hyperthyroidism have deleterious impacts on pregnancy and childhood outcomes, there is however no consensus on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and fetal health. Furthermore there is debate on the association between miscarriage and preterm delivery in euthyroid women positive for TPO antibodies. As a result the universal screening of pregnant women has not been recommended yet, as the benefits of identification of those subclinical for of thyroid disturbances has not been proved. There is not adequate data on cost-benefit of treatment of pregnant women suffer from subclinical thyroid disorders. Studies are now focusing on these controversial issues to produce critically needed data on the impact of treating these subclinical forms of thyroid disease on the mother, fetus, and the future intellect of the unborn child. The present review article is limited by not including the non-English articles. Summarizing the studies which have been published, the following can be concluded: 1) Overt hyperthyroidism and hypothyroidism have several adverse effects on pregnancy outcomes, 2) The long term effect of overt hypothyroidism on cognitive function has been well documented, 3) There is debate on short and long term effect of subclinical hypothyroidism, 4) Thyroid antibody positivity is associated with adverse pregnancy outcomes, but there is no consensus on feto-maternal complication of pregnant women with TPO antibody positive and euthyroid status. Future studies should include the following: 1) Studies of possible benefits of levo-T4 (LT4) in euthyroid and subclinical hypothyroidism women with positive TPO antibody; 2) Larger randomized control trials of patients with maternal hypothyroidism are necessary to impact on neurocognitive function; 3) More comprehensive studies with controlled iodine intake checks (urinary tests, for example) are suggested.
The authors report no declarations of interest.
Acknowledgment There was no involvement of a pharmaceutical or any other company in funding of this manuscript. There is no one in charge of medical writing or editorial assistance with the preparation of this article. 394
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thyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008; 112: 85-92. 34. Vissenberg R, Goddijn M, Mol BW, van der Post JA, Fliers E, Bisschop PH. Thyroid dysfunction in pregnant women: clinical dilemmas. Ned Tijdschr Geneeskd 2012; 56: A5163. 35. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and Subclinical Hypothyroidism Complicating Pregnancy. Thyroid 2002; 12: 63-68. 36. Idris I, Srinivasan R, Simm A, Page RC. Maternal hypothyroidism in early and late gestation: effects on neonatal and obstetric outcome. Clin Endocrinol 2005; 63: 560-565. 37. Wolfberg AJ, Lee-Parritz A, Peller AJ, Lieberman ES. Obstetric and neonatal outcomes associated with maternal hypothyroid disease. J Matern Fetal Neonatal Med 2005; 17: 35-38. 38. Hirsch D, Levy S, Nadler V, Kopel V, Shainberg B, Toledano Y. Pregnancy outcomes in women with severe hypothyroidism. Eur J Endocrinol 2013; 169: 313-320. 39. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341: 549-555. 40. Glinoer D, Soto MF, Bourdoux P, Lejeune B, Delange F, Lemone M, et al. Pregnancy in patients with mild thyroid abnormalities: maternal and neonatal repercussions. J Clin Endocrinol Metab 1991; 73: 421-427. 41. Glinoer D, Riahi M, Grün JP, Kinthaert J. Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol Metab 1994; 79: 197-204. 42. Stagnaro-Green A, Chen X, Bogden JD, Davies TF, Scholl TO. The thyroid and pregnancy: a novel risk factor for very preterm delivery. Thyroid 2005; 15: 351-357. 43. Benhadi N, Wiersinga WM, Reitsma JB, Vrijkotte TG, Bonsel GJ. Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death. Eur J Endocrinol 2009; 160: 985-991. 44. Karakosta P, Alegakis D, Georgiou V, Roumeliotaki T, Fthenou E, Vassilaki M, et al. Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J Clin Endocrinol Metab 2012; 97: 4464-4472. 45. Stagnaro-Green A. Thyroid antibodies and miscarriage: where are we at a generation later? J Thyroid Res 2011; ID 841949. 46. Negro R, Formoso G, Coppola L, Presicce G, Mangieri T, Pezzarossa A, et al. Euthyroid women with autoimmune disease undergoing assisted reproduction technologies: the role of autoimmunity and thyroid function. J Endocrinol Invest 2007; 30: 38. 47. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, Vijlder JJ. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol 2003; 59: 282-288. 48. Kooistra L, Crawford S, van Baar AL, Brouwers EP, Pop VJ. Neonatal effects of maternal
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Review article
Thyroid dysfunction and pregnancy outcomes Sima Nazarpour1 Ph.D. Candidate, Fahimeh Ramezani Tehrani2 M.D., Masoumeh Simbar1 Ph.D., Fereidoun Azizi3 M.D. 1. Department of Reproductive Health, Faculty of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Corresponding Author: Fahimeh Ramezani Tehrani, Research Institute for Endocrine Sciences, 24 Parvaneh, Yaman St., Velenjak, Tehran, Iran. P.O.Box: 19395-4763. Email: [email protected]; [email protected] Tel: (+98) 21-22409309 Received: 4 March 2014 Revised: 30 November 2014 Accepted: 18 March 2015
Abstract Background: Pregnancy has a huge impact on the thyroid function in both healthy women and those that have thyroid dysfunction. The prevalence of thyroid dysfunction in pregnant women is relatively high. Objective: The objective of this review was to increase awareness and to provide a review on adverse effect of thyroid dysfunction including hyperthyroidism, hypothyroidism and thyroid autoimmune positivity on pregnancy outcomes. Materials and Methods: In this review, Medline, Embase and the Cochrane Library were searched with appropriate keywords for relevant English manuscript. We used a variety of studies, including randomized clinical trials, cohort (prospective and retrospective), case-control and case reports. Those studies on thyroid disorders among non-pregnant women and articles without adequate quality were excluded. Results: Overt hyperthyroidism and hypothyroidism has several adverse effects on pregnancy outcomes. Overt hyperthyroidism was associated with miscarriage, stillbirth, preterm delivery, intrauterine growth retardation, low birth weight, preeclampsia and fetal thyroid dysfunction. Overt hypothyroidism was associated with abortion, anemia, pregnancy-induced hypertension, preeclampsia, placental abruption, postpartum hemorrhage, premature birth, low birth weight, intrauterine fetal death, increased neonatal respiratory distress and infant neuro developmental dysfunction. However the adverse effect of subclinical hypothyroidism, and thyroid antibody positivity on pregnancy outcomes was not clear. While some studies demonstrated higher chance of placental abruption, preterm birth, miscarriage, gestational hypertension, fetal distress, severe preeclampsia and neonatal distress and diabetes in pregnant women with subclinical hypothyroidism or thyroid autoimmunity; the other ones have not reported these adverse effects. Conclusion: While the impacts of overt thyroid dysfunction on feto-maternal morbidities have been clearly identified and its long term impact on childhood development is well known, data on the early and late complications of subclinical thyroid dysfunction during pregnancy or thyroid autoimmunity are controversial. Further studies on maternal and neonatal outcomes of subclinical thyroid dysfunction maternal are needed. Key words: Thyroid disease, Pregnancy outcome, Hypothyroidism, Hyperthyroidism. This article extracted from Ph.D. thesis. (Sima Nazarpour)
Introduction hyroid hormones have profound variation during the life span and are associated with severe adverse health impacts (1, 2). Pregnancy, as an important reproductive event, has a profound but reversible effect on the thyroid gland and its functions. Pregnancy is actually a state of excessive thyroid stimulation leading to an increase in thyroid size by 10% in iodide sufficient areas and 20-40% in iodide deficient regions (3). Furthermore following the physiological and hormonal changes caused by pregnancy and human chorionic gonadotropin (HCG) the production of thyroxin
T
(T4) and triiodothyronine (T3) increase up to 50% leading to 50% increase in a woman’s daily iodide need, while Thyroid-stimulating hormone (TSH) levels are decreased, especially in first trimester (4). In an iodide sufficient area, these thyroid adaptations during pregnancy are well tolerated, as stored inner thyroid iodide is enough; however in iodide deficient areas, these physiological adaptations lead to significant changes during pregnancy (5). Furthermore in women who suffered from thyroid dysfunction prior to pregnancy, the hormonal changes mentioned are magnified, leading to possibly adverse pregnancy outcomes if not been treated appropriately. Furthermore the mode of delivery may
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additionally have adverse impact on fetalpituitary- thyroid axis (6). The prevalence of thyroid dysfunction in pregnant women is relatively high so that overt thyroid dysfunction occurs in 2-3% of pregnancies, and subclinical dysfunction in 10% of pregnancies (7) and thyroid autoimmunity is even more prevalent (8). Given the high prevalence of thyroid disturbances in pregnancy and lack of adequate review article summarizing the effect of thyroid dysfunction on pregnancy and neonatal outcomes, we aimed to summarize the adverse effects of thyroid dysfunction including hyperthyroidism, hypothyroidism and thyroid autoimmune positivity on pregnancy outcomes. Research question was: "are thyroid disorders in pregnant women associated with adverse effects on pregnancy outcomes"? Evidence acquisition This review study was conducted with a prospective protocol. We searched Medline (1985-2013), Embase (1985-2013) and the Cochrane Library (2012) for relevant English manuscripts. Using keywords including “thyroid”, “thyroid dysfunction”, “thyroid disorder”, “hyperthyroidism”, “hypothyroidism”, “euthyroidism”, “subclinical hypothyroidism”, “subclinical hyperthyroidism”, “thyroid autoantibodies”, “pregnancy outcome”, “miscarriage”, “abortion”, “pregnancy loss”, “preterm”, “premature”, “early labor”, “Thyroid peroxidase” and “cognitive” to generate a subset of citations relevant to our research question. Subclinical hypothyroidism (SCH) is defined as a serum TSH level above the
upper limit of normal despite normal levels of serum free thyroxine and subclinical hyperthyroidism is defined as serum thyroid hormone levels within their respective reference ranges in the presence of lowundetectable serum TSH levels (9). Overt hypothyroidism is defined as a serum free T4 level lower than the upper limit of normal and overt hyperthyroidism is defined as a serum free T4 level above the upper limit of normal. Thyroid autoimmunity is defined as increase in thyroid auto antibodies above the upper limit of normal with or without thyroid disturbances. The full manuscripts of all citations that met our study objective were selected and obtained. In cases of duplicate publications, we selected the most recent and complete versions. From the 4480 citations identified from electronic searches, at the beginning, we found 512 related articles; 130 studies on overt hypothyroidism, 203 on subclinical hypothyroidism, 69 on overt hyperthyroidism, 43 on subclinical hyperthyroidism, and 67 on thyroid immunity. Of these articles, 58 met our study objectives, including 11 on hyperthyroidism, 22 on hypothyroidism and 26 on thyroid immunity. We included all qualified original articles on our study subject; including randomized clinical trials, cohort (prospective and retrospective), case-control and case reports. We excluded non-English manuscript, those conducted on non-pregnant women and those with poor quality methodology. The titles and abstracts of all of the studies were evaluated by two non-dependent persons and those met inclusion criteria were appraised.
512 Articles on thyroid dysfunctions
Overt hypothyroidism n=130
Subclinical hypothyroidism n=203
Overt hyperthyroidism n=69
Hypothyroidism In pregnancy n=22
Subclinical hyperthyroidism n=43
Hyperthyroidism In pregnancy n=11
Thyroid immunity n=67
Thyroid immunity In pregnancy n=26
Figure 1. The number of articles that were reviewed in the study.
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Thyroid dysfunction in pregnancy
Results Hyperthyroidism and its adverse pregnancy and neonatal outcomes The natural physiological changes during pregnancy can mimic some of the signs observed in hyperthyroidism, including increased in basal metabolism, heart rate, fatigue, anxiety, palpitations, heat intolerance, warm and wet skin, hand tremors and systolic murmur; as a result the diagnosis of hyperthyroidism during pregnancy could cause clinical difficulties (9-11). Pregnant women, who suffer from hyperthyroidism, have more severe tachycardia and thyromegaly, along with exophthalmia, and lack of weight gain despite receiving adequate food (10). Overt hyperthyroidism during pregnancy was not prevalent and was reported in 2 out of 1000 pregnancies (0.2%), while subclinical hyperthyroidism was occurred in 1.7% of pregnancies (11, 12). The most prevalent reason for hyperthyroidism during pregnancy was the transient hyperthyroidism resulting from hyperemesis gravidarum (THHG) due to the thyroid stimulation of beta-HCG (13); it was more prevalent in Asian populations compared to Europeans (14). Except for THHG, the etiologies of thyrotoxicosis during pregnancy are the same as for non-pregnant women; it is most prevalent in Grave’s Disease caused by thyrotropin receptor antibodies stimulating the thyroid (TRabs) (11, 15). It is well documented that overt hyperthyroidism has several adverse effects on pregnancy outcomes, e.g. miscarriage, stillbirth, preterm delivery, intrauterine growth retardation, preeclampsia (11, 16). Furthermore women with Graves' disease have antibodies that can stop or stimulate the fetal anti-TSH receptor of thyroid gland (15, 17, 18). There is no consensus regarding the adverse effect of subclinical hypothyroidism on pregnancy or neonatal outcomes. Casey et al. reported no significant increase of placenta abruption, preterm labor and low birth weight in pregnancy complicated by subclinical hyperthyroidism in comparison with euthyroid ones (19). Table I summarizes the results of the most relevant studies on the impact of overt and subclinical hyperthyroidism on pregnancy and neonatal outcomes.
Hypothyroidism and its adverse pregnancy and fetal outcomes Pregnancy can imitate some of the signs that are observed in hypothyroidism, including fatigue, anxiety, constipation, muscle cramps, and weight gain; as a result, the clinical diagnosis of hypothyroidism during pregnancy may be difficult (10, 27). Moreover, most signs of hypothyroidism can be hidden by a woman’s status following the increase in metabolism in pregnancy. Furthermore the thyroid hormonal profile in normal pregnancy can be mis-interoperated as hypothyroidism and as a result the interpretation of thyroid function tests needs trimester-specific reference intervals for a specific population (14, 15). Applying trimester-specific reference ranges of thyroid hormones prevents misclassification of thyroid dysfunction during pregnancy. Compared to hyperthyroidism, hypothyroidism is very common during pregnancy; 2-3% of pregnant women suffer from hypothyroidism (0.3-0.5% overt hypothyroidism and 2-2.5% subclinical hypothyroidism) (11, 28). While the main etiology for hypothyroidism during pregnancy worldwide is iodide insufficiency, however in iodide sufficient areas its main cause is autoimmune thyroiditis (8). SCH is the most common thyroid dysfunction during pregnancy (11, 29). Its prevalence varies between 1.5-5% based on various definitions, different ethnicity, iodine consumption and nutrition life style as well as study designs (30). While the adverse effects of SCH accompanied with positive TPO antibodies or overt hypothyroidism on pregnancy outcome are well known, however there is controversy on negative impact of SCH without autoimmunity on pregnancy outcomes (27, 31-33). Pregnant women that possess the TPO antibodies during the initiation of their pregnancy are subjected to subclinical hypothyroidism during their pregnancy or thyroid dysfunction after childbirth (12). Table II and III summarize the studies on adverse outcomes of overt and subclinical hypothyroidism, respectively. As it has been shown the overt hypothyroidism is associated with increase in prevalence of abortion, anemia, pregnancy-induced hypertension, preeclampsia, placental abruption, postpartum hemorrhage, premature birth, low birth weight,
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intrauterine fetal death and neonatal respiratory distress (15, 27, 29, 32, 34-41). There is no consensus on adverse impacts of subclinical hypothyroidism on pregnancy outcomes; while some studies demonstrated higher chance of placental abruption, preterm birth, miscarriage, gestational hypertension, fetal distress, severe preeclampsia and neonatal distress and diabetes, the other study have not reported and adverse effect (31, 33, 42, 43, 45, 46). The long term effect of overt hypothyroidism on cognitive function has been well documented; these children have lower IQ and more developmental dysfunction (8, 12, 15, 38-41, 46-48), however there is no consensus on the long term cognitive effects of subclinical hypothyroidism; while some reported loss of motor function and intelligence in infants and children the other reported a normal motor and cognitive function (15, 45, 48, 50, 51). Table IV summarizes the cognitive function of infants and children been affected by overt or subclinical hypothyroidism during pregnancy. Autoimmune thyroid disorders Anti-thyroid antibodies are relatively common among women during their reproductive ages, 6-20% of all euthyroid
women are positive for anti-thyroid antibodies (8). The presence of anti-thyroid antibodies during a woman’s reproductive age is not necessarily followed by a thyroid dysfunction and 10-20% of all pregnant women who are TPO antibody positive remain euthyroid in first trimester (3, 56). Despite the high prevalence of TPO antibody positive among reproductive age women, there is no consensus on the feto-maternal complications of euthyroid pregnant women who are TPO antibody positive. As a result, routine screening of pregnant women for thyroid antibodies is controversial (57, 58). Table 7 summarizes the results of the most relevant studies regarding the feto-maternal outcomes of thyroid autoimmune positivity in euthyroid women. While adverse outcomes such as abortion, preterm delivery, recurrent miscarriage, hypertension, fetal dyspenea and diabetes are reported in some of studies, other studies report compatible pregnancy outcomes (27, 40, 44, 45, 46, 59-66). Furthermore Ghassabian and Tiemeier showed that the high titration of anti-thyroid peroxidase antibodies (TPO-Ab) during pregnancy associated with an increased risk of cognitive and behavioral problems in preschool children (67).
Table I. The adverse effects of hyperthyroidism (overt/subclinical) on pregnancy and neonatal outcomes Authors
Year of publication
Location
Type of study
Participants
Outcome
Overt hyperthyroidism Davis et al. (20) Kriplani et al. (21)
1989
USA
Prospective
60 Pregnant women with overt thyrotoxicosis
small for gestational age births, stillbirths, and possibly congenital malformations Preterm labor, pregnancy induced hypertension thyroid crisis, intrauterine growth retardation. Abnormal Thyroid status of neonates.
1994
India
Prospective
32 pregnancies complicated by hyperthyroidism
1994
USA
Retrospective
181 hyperthyroid pregnant women
Low birth weight infants and severe preeclampsia.
2001
Thailand
Retrospective
293 pregnant women with present and past history of hyperthyroidism
Low birth weight
Peleg et al. (18)
2002
USA
Retrospective
Twenty-nine women with a history of Graves disease and positive thyroid-stimulating immunoglobulin
Neonatal thyrotoxicosis
Polak et al. (17)
2004
France
Prospective
72 pregnant women with a history of Graves' disease.
Fetal goiter
Luton et al. (24)
2005
France
prospective
72 pregnant women (72 fetuses)
One fetus had moderate hypothyroidism (1 fetus), goiter (11 fetuses at 32 weeks), and fetal thyroid dysfunction
Luewan et al. (25)
2011
Thailand
Prospective (cohort)
540 pregnant women (180 with hyperthyroidism and 360 controls)
Fetal growth restriction, preterm birth and low birth weight, tendency to have a higher rate of pregnancy-induced hypertension.
Männistö et al. (26)
2013
USA
Retrospective (cohort)
223512 singleton pregnancies
Preeclampsia, superimposed preeclampsia, preterm birth, induction, neonatal intensivecare unit admission
USA
Prospective (cohort)
Millar et al. (22) Phoojaroench anachai et al. (23)
Casey et al. (19)
390
2006
Subclinical hyperthyroidism A total of 25,765 women underwent thyroid screening and 433 women were considered to have subclinical hyperthyroidism
Subclinical hyperthyroidism is not associated with adverse pregnancy outcomes
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Thyroid dysfunction in pregnancy
Table II. The adverse effects of overt hypothyroidism on pregnancy outcomes Authors
Year of publication
Location
Type of study
Participants
Outcomes Abortion, premature delivery
Abalovich et al (35)
2002
Argentina
Randomized Clinical Trial
114 women with primary hypothyroidism (16 overt hypothyroidism)
Wolfberg et al (37)
2005
USA
Retrospective
19,969 women (482 with treated hypothyroid disease and 19,487 without thyroid disease)
Pre-eclampsia
Idris et al (36)
2005
England
Retrospective
167 pregnant women
Low birth weight caesarean section
Cleary Goldman et al (33)
2008
USA
Prospective
10,990 pregnant women
Preterm labor , macrosomia, gestational diabetes
Sahu et al (32)
2010
India
Prospective
633 pregnant women
Pregnancy-induced hypertension, intrauterine growth restriction, intrauterine demise, Neonatal complications, gestational diabetes
Hirsch et al (38)
2013
Israel
Retrospective case series
306 pregnant women (101 with hyperthyroidism and 205 euthyroid)
Abortions and premature delivery
223512 singleton pregnancies
Primary hypothyroidism: Preeclampsia, superimposed preeclampsia, gestational diabetes, preterm birth, induction , cesarean section, intensive-care unit admission Iatrogenic hypothyroidism: placental abruption , breech presentation, cesarean section after spontaneous labor
Männistö et al (26)
2013
USA
Retrospective
Table III: The adverse effects of subclinical hypothyroidism (with/without thyroid autoimmunity) on pregnancy outcomes Year of publication
Location
2002
Argentina
2005
USA
Prospective (nested-case control)
953 women
Very preterm delivery
2005
USA
Prospective
25,756 women
Placental abruption Preterm birth
ClearyGoldman et al (33)
2008
USA
Prospective
10,990 patients
Subclinical hypothyroidism was not associated with adverse outcomes.
Sahu et al (32)
2010
India
Prospective
633 women
Cesarean section rate for fetal distress
Wilson et al (31)
2012
USA
Prospective
24,883 women
Severe preeclampsia
Authors
Abalovich et al (35) StagnaroGreen et al (42) Casey et al (29)
Negro et al (27)
Benhadi et al (43)
Karakosta et al (44)
2006
2009
2012
Type of the Participants study Subclinical hypothyroidism without control of TPOAb 114 women with primary hypothyroidism (35 subclinical Prospective hypothyroidism
Outcomes
Abortion, premature delivery
Subclinical hypothyroidism including negative and positive TPO Ab Pregnant women who are positive for TPOAb develop impaired thyroid Randomized Italy 984 pregnant women function, increased risk of miscarriage Clinical Trial and premature deliveries Netherlan ds
Greece
prospective (cohort)
prospective
2497 women
Pregnant women without overt thyroid dysfunction, the risk of child loss increased with higher levels of maternal TSH
1170 pregnant women
Increased gestational diabetes and low birth weight neonates among those with of high TSH and spontaneous preterm among those without elevated TSH levels
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Nazarpour et al
Table IV: The cognitive function of infants and children been affected by overt or subclinical hypothyroidism during pregnancy Authors
Year of publication
Location
Type of the study
Participants
Result
Overt hypothyroidism Liu et al (52)
1994
China
All children showed normal IQs Adversely affect their children's
Haddow et al (39)
1999
England
Prospective (cohort)
25216 women
subsequent performance on neuropsychological tests.
125 children of women with Pop et al (47)
2003
Netherlan ds
Prospective
hypothyroxinaemia (63 cases and 62
Delay in infant neurodevelopment.
controls) 204 (108 neonates who were born to
Kooistra et al (48)
2006
Netherlan
Retrospective
ds
(case control)
mothers with hypothyroidism and 96 control)
Lower scores on the Neonatal Behavioral Assessment Scale and orientation index
213 (18 isolated subclinical Li et al (50)
2010
China
Prospective
hypothyroidism, 19 hypothyroxinaemia,
Lower motor and intellectual
(cohort)
34 euthyroid TPOAb positive and 142
development at 25-30 months.
controls) Prospective Henrichs et al (49) Chevrier et al (53)
2010
2011
Netherlan ds
USA
(Population-
Higher risk of expressive language and 3659 children and their mothers
nonverbal cognitive delay
based cohort) Prospective (cohort)
No adverse effect on child 287 pregnant women and their children
neurodevelopment. Children had average or above average results on all parameters. Comparative scores of the neuropsychological tests in
Downing et al (54)
2012
USA
Case report
Three women with hypothyroidism
sibling pairs for full-scale IQ and performance IQ were variable; some scores were higher and some lower in children with congenital hypothyroidism. The development scores (the TsumoriInage Infant's Developmental Test or the
Momotani et al (55)
2012
Japan
Case report
Five women with overt hypothyroidism
Wechsler Intelligence Scale) of all the children turned out to be either normal or advanced.
Subclinical hypothyroidism 213 (18 isolated subclinical Li et al (50)
2010
China
Prospective
hypothyroidism, 19 hypothyroxinaemia ,
Lower motor and intellectual
(cohort)
34 euthyroid TPOAb positive and 142
development at 25-30 months.
controls) Prospective
Ghorbani Behrooz et al (51)
392
2012
Iran
(Historical cohort)
62 children of mothers who had
No adverse effect on IQ level and
subclinical hypothyroidism
cognitive performance of children
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Thyroid dysfunction in pregnancy
Table V. The feto-maternal outcomes of thyroid autoimmune positivity in euthyroid pregnant women Year of publication
Location
Type of Study
Participants
Outcome
StagnaroGreen et al (68)
1990
USA
Prospective
552 pregnant women
Increased miscarriage
Glinoer et al (40)
1991
Belgium
Prospective
120 euthyroid pregnant women
Increased spontaneous abortion
Pratt et al (64)
1993
USA
Retrospective (case control)
45 women and 100 apparently health blood donors served as controls.
Increased recurrent spontaneous abortions
Glinoer et al (41)
1994
Belgium
Prospective
87 healthy pregnant women with thyroid antibodies and normal thyroid function
Increased spontaneous miscarriage and premature deliveries
Bussen et al (63)
1995
Germany
Retrospective
66 women (22 euthyroid non-pregnant habitual aborters; 22 nulligravidae and 22 multigravidae without endocrine dysfunction as controls).
Increased habitual abortions
Singh et al (69)
1995
Iijima et al (70)
1997
Authors
USA
Japan
Retrospective Prospective
487 subfertile women who had undergone Assisted reproductive technology 1, 179 healthy pregnant women including 228 cases of positive thyroid autoantibody
Increased miscarriage Increased spontaneous abortion
1999
USA
Retrospective.
1588 women (700 women with a history of pregnancy losses, 688 women with a history of infertility who were undergoing Assisted reproductive technology, and 200 healthy, reproductive-aged female controls)
1999
Netherlan ds
Prospective (nested-case control)
173 subfertile women undergoing Invitro fertilization
No increase of miscarriage in women without a history of habitual abortion
Dendrinos et al (60)
2000
Greece
Retrospective (case control)
45 women (30 euthyroid with Recurrent spontaneous miscarriage and 15 matched controls)
Increased recurrent spontaneous miscarriage
Bagis et al (59)
2001
Turkey
Retrospective
876 women
Poppe et al (71)
2003
Kutteh et al (62)
Muller et al (66)
Marai et al (72) StagnaroGreen et al (42) Negro et al (27) Ghafoor et al (73)
Retrospective (case control) Prospective (nested-case control) Randomized Clinical Trial
Pakistan
Prospective
1, 500 pregnant women
2007
Italy
Retrospective
416 euthyroid women (42 were positive TPOAb) undergoing Assisted reproductive technology
Increased unsuccessful pregnancy or subsequent miscarriage
2008
Iran
Retrospective (case-control)
641 women with a history of 3 or more consecutive pregnancy losses and 269 controls
Increased recurrent abortion
2008
USA
Prospective
10,990 pregnant women
Increased preterm premature rupture of membranes
2009
Finland
Prospective
9, 247 singleton pregnancies
Increased perinatal death
Iran
Retrospective (case control)
95 cases as fertile controls and 70, 78 and 137 cases with infertility and recurrent abortion respectively.
Increased recurrent abortion
USA
Prospective
10, 062 singleton pregnancies
2011
Italy
Prospective
3593 pregnant women
2011
India
Prospective
483 pregnant women
Israel
2005
USA
2006
Italy
2006
Negro et al (46) Iravani et al (74)
Soltanghora ee et al (76) Haddow et al (77) Negro et al (78) Nambiar et al (61) Ashoor et al (65) Karakosta et al (44)
Increased abortion
234 subfertile women undergoing Assisted reproductive technology 66 women (58 with impaired fertility and 28 control parous women) 124 Cases and 124 Controls were randomly selected from among the 953 women who delivered at term 984 pregnant women (TPO Ab + & -, euthyroid & subclinical)
Belgium
2004
ClearyGoldman et al (33) Männistö et al (75)
Increased recurrent pregnancy loss
2010 2010
Prospective,
2011
Europe
Prospective
4, 420 singleton pregnancies
2012
Greece
Prospective
1170 pregnant women (TPO Ab + & - , euthyroid & subclinical)
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Increased miscarriage Increased recurrent miscarriages Increased very preterm delivery Increased miscarriage and premature deliveries Increased low-birth-weight of neonates and high abortion rate
Increased preterm delivery, premature rupture of membranes Increased very preterm delivery and respiratory distress Increased miscarriage No increase spontaneous early preterm delivery Increased gestational diabetes and low birth weight neonates among those with of high TSH and spontaneous preterm among those without elevated TSH levels
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Conclusion
Conflict of Interests
Although it is well documented that overt hypothyroidism and overt hyperthyroidism have deleterious impacts on pregnancy and childhood outcomes, there is however no consensus on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and fetal health. Furthermore there is debate on the association between miscarriage and preterm delivery in euthyroid women positive for TPO antibodies. As a result the universal screening of pregnant women has not been recommended yet, as the benefits of identification of those subclinical for of thyroid disturbances has not been proved. There is not adequate data on cost-benefit of treatment of pregnant women suffer from subclinical thyroid disorders. Studies are now focusing on these controversial issues to produce critically needed data on the impact of treating these subclinical forms of thyroid disease on the mother, fetus, and the future intellect of the unborn child. The present review article is limited by not including the non-English articles. Summarizing the studies which have been published, the following can be concluded: 1) Overt hyperthyroidism and hypothyroidism have several adverse effects on pregnancy outcomes, 2) The long term effect of overt hypothyroidism on cognitive function has been well documented, 3) There is debate on short and long term effect of subclinical hypothyroidism, 4) Thyroid antibody positivity is associated with adverse pregnancy outcomes, but there is no consensus on feto-maternal complication of pregnant women with TPO antibody positive and euthyroid status. Future studies should include the following: 1) Studies of possible benefits of levo-T4 (LT4) in euthyroid and subclinical hypothyroidism women with positive TPO antibody; 2) Larger randomized control trials of patients with maternal hypothyroidism are necessary to impact on neurocognitive function; 3) More comprehensive studies with controlled iodine intake checks (urinary tests, for example) are suggested.
The authors report no declarations of interest.
Acknowledgment There was no involvement of a pharmaceutical or any other company in funding of this manuscript. There is no one in charge of medical writing or editorial assistance with the preparation of this article. 394
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